In this application, we propose to treat liver carcinoma in vivo, in a rabbit VX2 model, using TiO2 based composite nanoconjugates. During the previous funding period, this application was dedicated to the development of TiO2-biopolymer nanoconjugates as new vehicles for biotechnology. These studies found that, dependent on the nanoparticle coating, these nanoconjugates caused DNA scission or interacted with cellular proteins. Both of these activities can be used to interfere with cancer maintenance and progression. In addition, we have developed novel nanocomposites and nanoconjugate formulations that provide increase photocatalytic activity and modulate contrast for magnetic resonance imaging, leading to improved therapeutic potential and allowing for monitoring of composite nanoconjugate's delivery and retention. We now propose to combine these approaches and the rabbit liver carcinoma VX2 model, a cancer that develops due to papilloma virus infection, in order to attempt to use nanoconjugates therapeutically. We will pursue papilloma virus genome targets not only because they provide tumor- specific markers in this system but also because of their relevance to a portion of head and neck tumors and cervical carcinoma which are similarly infected; it is also quite possible that other tumor systems will be shown to have papilloma virus involvement as well. In addition, this system will provide a model for providing information on non-papilloma virus induced tumors and liver metastatic disease. The specific aims of this proposal are: AIM 1. Formulating composite nanoconjugates (CNCs) optimal for E6/E7 control of papilloma transformed cells and for ROS mediated cell destruction. AIM 2. Formulating the optimal combination of CNCs, scintillator nanoparticles and irradiation for E6/E7 control of papilloma transformed cells and for ROS mediated cell destruction. AIM 3. Testing the curative capacity of the two most optimal combinations of CNCs and scintillator NPs at different timepoints post irradiation Rabbit liver carcinoma is a particularly interesting animal model because it mimics well human liver carcinoma and interventional radiology approaches to deliver non-surgical interventions. Namely, the rabbit VX2 tumor model resembles human disease in that it has the disease- characteristic vasculature (the hepatic artery delivers blood to the tumor), and there exists the possibility of using a catheter to deliver therapeutics. In addition, virally induced cancers are an attractive model for targeting with nanoconjugates. Any breakthrough in this system could therefore aid in pursuit of anti-cancer therapies in papilloma induced cancers such as cervical and head and neck cancer. PUBLIC HEALTH RELEVANCE: The rabbit liver carcinoma model VX2 will be used to investigate the therapeutic potential of nanocomposites Fe3O4@TiO2-biopolymer (peptide nucleic acids and peptides) nanoconjugates against cancer. Papilloma virus expression is the cause of this liver carcinoma; tumor cells and viral genes and proteins will be targeted by composite nanoconjugates. The ability of composite nanoconjugates to target the tumor tissue, cause viral genome damage and tumor cell death will be tested in rabbits in vivo.